Disease relevance of FKBP1A

• FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models, showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases [1].
• In the context of the high expression of FKBP38 in neuroblastoma cells, these data suggest that FKBP38.CaM/Ca(2+) inhibition can mediate neurotrophic properties of FKBP ligands [1].
• This effect was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP [2].
• The human FKBP cDNA sequence shows significant similarity to an open reading frame in the Neisseria meningitidis genome [3].
• They further suggest a pathophysiological role for FKBP12 as a mediator in immediate or type I hypersensitivity and may have implications for novel therapeutic strategies in the treatment of allergic disorders with FK506 and rapamycin [4].

Psychiatry related information on FKBP1A

• This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder [5].

High impact information on FKBP1A

• This procedure involves coexpressing an FKBP-tagged Golgi enzyme with an ER-retained protein fused to FRAP in COS cells [6].
• FKBP12 binds to the GS region of the receptor, capping the TbetaR-II phosphorylation sites and further stabilizing the inactive conformation of TbetaR-I [7].
• Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12 [7].
• The crystal structure of a fragment of unphosphorylated TbetaR-I, containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12 [7].
• The human rotamase or peptidyl-prolyl cis-trans isomerase Pin1 is a conserved mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle [8].

Chemical compound and disease context of FKBP1A

• Peptidyl-prolyl cis-trans isomerase of Bacillus subtilis: identification of residues involved in cyclosporin A affinity and catalytic efficiency [9].
• This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia [10].
• An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1, were viable and fully resistant to rapamycin and (ii) FK506 antagonized rapamycin toxicity in vivo [11].
• A biotinylation signal sequence was fused to the 5' end of the human FKBP12 gene, and the fusion protein was expressed in Escherichia coli with biotin ligase [12].
• The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1) [5].

Biological context of FKBP1A

• ATP/GTP binding likely occurs within the second FKBP-like domain, near the FK506 binding site on the FKBP template [13].
• A third domain detected by the hydrophobic cluster analysis method is distantly structurally related to the two first FKBP-like domains and is followed by the C-terminal part of the protein, which contains a calmodulin binding consensus sequence [13].
• We demonstrate that the resonse to rapamycin in yeast cells is mediated by a gene encoding a 114-amino-acid, approximately 13-kDa protein which has a high degree of sequence homology with human FKBP; we designated this gene RBP1 (for rapamycin-binding protein) [14].
• The ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum of skeletal muscle is comprised of four 565,000-dalton RyR1s, each of which binds one FK506 binding protein (FKBP12) [15].
• Co-expression of FKBP12.6, but not FKBP12, or incubation of cells with ryanodine suppressed intracellular Ca2+ flux and restored normal cell viability and proliferation [16].

Anatomical context of FKBP1A

• Rotamase assays and immunoblot analysis of subcellular fractions indicate the presence of a CyP isoform in the stroma of chloroplasts but not in the thylakoid membranes or thylakoid lumen [17].
• The predicted protein features the two FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase) signatures and an endoplasmic reticulum retention signal [18].
• FKBP binding characteristics of cardiac microsomes from diverse vertebrates [19].
• This review focuses on studies showing that systemic administration of FK506 dose-dependently speeds nerve regeneration and functional recovery in rats following a sciatic-nerve crush injury [20].
• Expression of FKBP12 and ryanodine receptors (RyRs) in the spinal cord of MND patients [21].

Associations of FKBP1A with chemical compounds

• In vitro chloroplast import of precursors of other chloroplast proteins was unaffected by concentrations of cyclosporin A which completely inhibit rotamase activity of chloroplast stromal CyP [17].
• We now show that substitution of a Gly, Glu, or Ile for Val2461 in RyR1 prevents FKBP12 binding to RyR1, resulting in channels with increased gating frequency [15].
• Substitution of Val(2322) for leucine (as in IP(3)R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val(2322) for aspartate completely abolished the FKBP interaction [22].
• Energetic and structural analysis of the role of tryptophan 59 in FKBP12 [23].
• This FK506-FKBP complex inhibits the activity of the serine/threonine protein phosphatase 2B (calcineurin), the basis for the immunosuppressant action of FK506 [20].

Physical interactions of FKBP1A

• FKBP12 binding modulates ryanodine receptor channel gating [15].
• FKBP6 shows homology to the FK-506 binding protein (FKBP) class of immunophilins [24].
• A simple model system based on the effect of FK 506 on isolated rat pancreatic islets was utilised to study the relationship between inhibition of insulin biosynthesis, inhibition of interleukin 2 (IL-2) activation and FK binding protein (FKBP-12) binding of FK 506 and a number of FK 506 analogues [25].
• Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity [26].
• More specifically, we find that amino acids 400-420 play a critical role for Hsp90 binding by either FKBP [27].

Regulatory relationships of FKBP1A

• There was negligible hRyR2-induced subcellular redistribution of FKBP12 [28].
• The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP [29].
• Whereas FKBP12 inhibited EGF receptor tyrosine kinase activity in a concentration-dependent manner, the cyclophilins did not affect autophosphorylation [30].
• Finally, we demonstrate that FK506 and fluconazole have synergistic activity that is independent of both FKBP12 and calcineurin and may involve the known ability of FK506 to inhibit multidrug resistance pumps, which are known to export azoles from fungal cells [31].
• The FKBP12 expression increased during ATRA-induced differentiation and expression of cyclophilin A remained unchanged [32].

Other interactions of FKBP1A

• Whereas the binding of calcineurin to FKBP12 is potentiated by FK506, the specific association of PAHX and FKBP52 is maintained in the presence of FK506 [33].
• Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13 [34].
• FAP48 was identified and cloned thanks to its interaction with FK506-binding proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of immunophilins that bind the macrolide immunosuppressant drugs FK506 and rapamycin [35].
• For both RyRs, the stoichiometry is 4 FKBP/RyR [36].
• These molecular data are in agreement with the lack of correlation between FKBP12 and IP3R1 expression in various cell types [37].

Analytical, diagnostic and therapeutic context of FKBP1A

• Moreover, only a small fraction of the cellular pool of the major forms of cyclophilin or FKBP needs to be occupied by the drugs in order to achieve maximal immunosuppression [38].
• Moreover, immunoprecipitation experiments indicated a high-affinity interaction of FKBP12 with RyR1 but not with IP3R1 [37].
• The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography [39].
• In the course of protein engineering studies on human FKBP, we discovered that a single point mutation in the ligand-binding site (Phe-36 --> Met) converts the normally monomeric protein into a ligand-reversible dimer [40].
• In Northern blot analysis, mRNA species of approximately 1.8 kilobases that hybridized with human FKBP cDNA were detected in poly(A)+ RNAs from brain, lung, liver, and placental cells and leukocytes [41].

References